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J Thorac Cardiovasc Surg 1999;117:1-8
© 1999 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

TRANSGENE EXPRESSION AFTER ADENOVIRUS-MEDIATED RETRANSFECTION OF RAT LUNGS IS INCREASED AND PROLONGED BY TRANSPLANT IMMUNOSUPPRESSION

From the Thoracic Surgery Research Laboratory, Division of Thoracic Surgery, The Toronto Hospital Research Institute,^a Medical Research Council Group in Lung Development, Department of Paediatrics, The Hospital for Sick Children,^b and Division of Respiratory Medicine, Mount Sinai Hospital,^c University of Toronto, Toronto, Ontario, Canada.

This work was supported by a grant from the National Sanitarium Association of Canada. Dr Liu is a scholar of the Medical Research Council of Canada. Dr Boehler is a recipient of grants from the Swiss National Scientific Foundation and the Swiss Respiratory Society.

Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.

Received for publication April 6, 1998. Revisions requested June 23, 1998. Revisions received July 24, 1998. Accepted for publication Sept 8, 1998. Address for reprints: Shaf Keshavjee, MD, Division of Thoracic Surgery, The Toronto Hospital, EN-10-224, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.J Thorac Cardiovasc Surg 1999;117:1-7

Objectives: Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged.
Methods: Lewis rats underwent intratracheal adenovirus-mediated transfection with the ß-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection.
Results: After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P < .001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation.
Conclusions: Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administration of gene therapy.

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